According to one critic, Wisse's work has been characterized "by the sharpness of her insight, by her unwillingness to retreat from a skirmish and by the inability of even those who disagree with her to deny her brilliance."[5] She received one of the 2007 National Humanities Medals.[6] The award cited her for "scholarship and teaching that have illuminated Jewish literary traditions. Her insightful writings have enriched our understanding of Yiddish literature and Jewish culture in the modern world."[7]

In essays and in books like “If I Am Not for Myself: The Liberal Betrayal of the Jews” (1992) and “Jews and Power” (2008), Wisse has pursued a hard neo-Conservative line on social and political issues. She has angered feminists by arguing in favor of traditional marriage and gender roles, condemned Jewish participation in Communism and has highlighted Jewish culpability for its crimes. Wisse's criticism of the women's liberation movement as a form of neo-Marxism has been extensively cited by critics of radical feminist politics. She wrote:

Women's liberation, if not the most extreme then certainly the most influential neo-Marxist movement in America, has done to the American home what communism did to the Russian economy, and most of the ruin is irreversible. By defining relations between men and women in terms of power and competition instead of reciprocity and cooperation, the movement tore apart the most basic and fragile contract in human society, the unit from which all other social institutions draw their strength.[8]

"Most of all," according to a May 2014 profile in The Jewish Daily Forward Wisse has been "one of the most forceful conservative voices in support of Israel, arguing that criticism of the state repeats ingrained habits of Jewish accommodationism and self-blame."[9] She sees no moral equivalence between the Arab and Israeli sides in the Middle Eastern conflict:

There is no such thing as an Arab-Israel conflict,...there is an Arab war against Israel, there is an Arab war against the Jewish people’s right to a state.[10]

Wisse has been criticized for writing that "Palestinian Arabs [are] people who breed and bleed and advertise their misery"[11] in Commentary magazine in 1988.[12][13][14][15] According to Alexander Cockburn, Wisse is bothered by the "failure of nerve" of American Jewish intellectuals and their "squeamishness about the shootings and beatings meted out to the breeders."[12] Following protests and Harvard University's decision to cancel Marty Peretz's speech after Peretz wrote "Muslim life is cheap, especially to other Muslims",[16] Wisse condemned "Groupthink" at Harvard and defended Peretz, saying that "to wish that Muslims would condemn the violence in their midst is not bigotry but liberality".[17] Wisse is a member of the International Advisory Board of NGO Monitor.[18]